The intention of this project is to use the newly developed technology of gene targeting to produce a mouse strain with the same genetic lesion (a non-functional collagen 4a5 gene) as that recently found to be causative in X-linked Alport syndrome. This is a relatively common (1 in 5000), dominantly inherited genetic disorder that, in affected males, results in severe glomerulonephritis, and often times deafness and ocular manifestations (anterior lenticonis). Alport syndrome is a disease of the basement membrane which manifests itself in early childhood and usually results in death, due to kidney dysfunction, by late childhood or early adulthood. While much is known about basement membranes, the role of the newly discovered type 4 collagens (4a3, 4a4, and 4a5) in basement membrane assembly, remodeling and function have not been addressed to any satisfaction. It is difficult to address any questions on the ontogeny of basement membrane disease at the molecular level when working with human subjects. The proposed mouse model system would alleviate the problems of availability and genetic drift. Once derived and verified, we will subject the model to analysis using immunofluorescence, immunohistochemical techniques, electron microscopy, and electrophoretic and immunoblotting analysis of the purified protein components to address questions regarding the mechanism of the basement membrane lesions as a function of age and the progressive onset of the pathological symptoms.